1. Field of the Invention
The present invention concerns a process for obtaining d.sub.4 T polymorphic Form I from a mixture containing one or more of polymorphic Forms I, II and III.
2. Background Art
The compound d.sub.4 T (2',3'-didehydro-3'-deoxythymidine) has been approved for use in the treatment of AIDS. The drug has been named Stavudine by the USAN and is marketed as Zerit.RTM.. The structure is as follows: ##STR1##
The synthesis of this compound and its biological properties are described in T. S. Lin, et. al. U.S. Pat. No. 4,978,655 granted Dec. 18, 1990.
Other processes for making d.sub.4 T have been reported in the literature such as in Starrett, Jr. et. al. U.S. Pat. No. 4,904,770 granted Feb. 27, 1990.
In the course of preparing larger batch lots of d.sub.4 T for clinical testing, a problem was experienced in that the solubility of the compound was found to vary significantly from lot to lot. Since differences in solubility are consistent with different polymorphic forms, further investigation verified the existence of three solid state forms of d.sub.4 T, designated as Forms I, II, and III. Forms I and II are anhydrous polymorphs, whereas Form III is hydrated [(d.sub.4 T).sub.3 .multidot.H.sub.2 O] and is pseudopolymorphic with Forms I and II. Solid state transformation studies were performed under various stress conditions of moisture, heat, and vacuum. Form I is stable and shows no transformation to other polymorphic forms, thus demonstrating its greater thermodynamic stability relative to the other forms. However, Form III converted to Form I only when heated for 24 hours under vacuum at80.degree. C.
The capacity to occur in different crystal structures is known as polymorphism and is known to occur in many organic compounds including drugs. These different crystalline forms are known as "polymorphic modifications" or "polymorphs" and are realized only in the crystalline state. While polymorphic modifications have the same chemical composition, they differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. As such, these modifications may have different solid-state physical properties such as shape, color, density, harness, deformability, stability, dissolution properties, and the like. Polymorphism of an organic drug molecule and its consequences would be appreciated by one skilled in the pharmaceutical arts. As an example; Gordon, et. al. in U.S. Pat. No. 4,476,248, issued Oct. 7, 1984, disclosed and claimed a new crystalline form of the drug ibuprofen as well as the process for producing it. The new crystalline form was reported to improve the manufacturability of ibuprofen.
The issue of polymorphism is a well understood and critical aspect in the drug development process. In order to produce a solid state dosage form with predictable efficacy, dissolution properties, and stability (bulk and dosage stages), it is necessary to determine the existence of any solid state forms of the material and their respective solid state stability, dissolution, and thermodynamic properties. Subsequently, the proper form may be selected for development. All of these factors were considered in the development of d.sub.4 T.
Since Form I has been found to be the most thermodynamically stable form, with no tendency for solid state conversion to Form II or III, this is the form sold commercially as Zerit.RTM..
It is therefore an object of this invention to be able to reliably, conveniently and reproducibly prepare d.sub.4 T Form I.